Scientists fish for new epilepsy model and reel in potential drug

Sep. 3, 2013 — According to new research on epilepsy, zebrafish have certainly earned their stripes. Results of a study in Nature Communications suggest that zebrafish carrying a specific mutation may help researchers discover treatments for Dravet syndrome (DS), a severe form of pediatric epilepsy that results in drug-resistant seizures and developmental delays.Scott C. Baraban, Ph.D., and his colleagues at the University of California, San Francisco (UCSF), carefully assessed whether the mutated zebrafish could serve as a model for DS, and then developed a new screening method to quickly identify potential treatments for DS using these fish. This study was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health and builds on pioneering epilepsy zebrafish models first described by the Baraban laboratory in 2005.Dravet syndrome is commonly caused by a mutation in the Scn1a gene, which encodes for Nav1.1, a specific sodium ion channel found in the brain. Sodium ion channels are critical for communication between brain cells and proper brain functioning.The researchers found that the zebrafish that were engineered to have the Scn1a mutation that causes DS in humans exhibited some of the same characteristics, such as spontaneous seizures, commonly seen in children with DS. Unprovoked seizure activity in the mutant fish resulted in hyperactivity and whole-body convulsions associated with very fast swimming. These types of behaviors are not seen in normal healthy zebrafish.”We were also surprised at how similar the mutant zebrafish drug profile was to that of Dravet patients,” said Dr. Baraban. “Antiepileptic drugs shown to have some benefits in patients (such as benzodiazepines or stiripentol) also exhibited some antiepileptic activity in these mutants. …

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Newly identified genetic factors drive severe childhood epilepsies

Aug. 11, 2013 — Researchers have identified two new genes and implicated 25 distinct mutations in serious forms of epilepsy, suggesting a new direction for developing tailored treatments of the neurological disorders.The findings by an international research collaboration, which includes investigators from Duke Medicine, appear Aug. 11 in the journal Nature.Epileptic encephalopathies are a devastating group of severe brain disorders characterized by the onset of seizures at an early age. The seizures are often accompanied by cognitive and behavioral issues, which can hinder the quality of life of affected children and their families.The cause of epileptic encephalopathies is largely unknown; while genes are believed to play an important role, specific genes have only been identified in a small number of cases.”One important aspect of the study is that we identified an unusually large number of distinct disease-causing mutations — 25 in total, all of which were de novo mutations. These mutations will be an invaluable resource to scientists working to elucidate the underlying causes of the epilepsies,” said study author David Goldstein, PhD, director of the Duke Center for Human Genome Variation.A de novo mutation is a new alteration in a gene that appears for the first time in a family, and results from a genetic mutation in a parent’s germ cell (egg or sperm).Learning more about the disorders’ origin will guide development of effective therapies, which is the goal of Epi4K, an international research consortium funded by the National Institute of Neurological Diseases and Stroke (NINDS).”This research focusing on epileptic encephalopathies is the first large-scale project of Epi4K,” said study author Erin Heinzen, PhD, assistant professor of medicine in the Division of Medical Genetics at Duke. “The study was designed to identify de novo mutations and search for ones that contribute to risk.”The Epi4K researchers partnered with the Epilepsy Phenome/Genome Project, another NINDS-funded group working to unlock the mysteries of epilepsy. Led by Daniel Lowenstein, M.D., professor of neurology at the University of California, San Francisco, the researchers in the Epilepsy Phenome/Genome Project gathered genetic information on 264 children with epileptic encephalopathies and their parents.The Epi4K researchers then focused on identifying all new mutations in the children using next-generation sequenced data, which looks at the part of genome that encodes protein. The Center for Human Genome Variation at Duke conducted this analysis, and confirmed 329 de novo mutations. Most of these mutations had no connection to the risk of disease, but the researchers showed that a fraction of them strongly influence risk.The researchers saw that the genes already known to cause epileptic encephalopathies carried multiple de novo mutations. However, they found multiple de novo mutations in two additional genes- GABRB3 and ALG13 — not previously connected to epileptic encephalopathies. …

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